Soluble polymers bearing pendant amphiphilic or hydrophobic groups, commonly known as polysoaps, have been studied for a number of years and numerous applications proposed1 based on exploiting their solubilisation capacity for hydrophobic molecules2, 3. These compounds form intramolecular micelles4, 5, usually several per molecule6, and their solubilisation capacity is not lost on dilution1 unlike small molecular weight micelles7, making them especially useful as solubilisers. Although these molecules are well known they have not been exploited to any great extent as pharmaceutical solubilisers.
Hydrophobic drugs are those drugs, which are practically insoluble in water. The definition of “practically insoluble” used by the British Pharmacopoeia is used here and is defined as a situation where 1 g of such material requires more than 10,000 millilitres of solvent (e.g. water) to be solubilised8 or alternatively a material which has a solubility of less than 0.1 mg mL−1 in water.
A few pharmaceutical solubilisers have been reported using hydrophobically and hydrophilically modified chitosans, namely: N-acyl 6-sulphated chitosans10, quaternary ammonium palmitoyl glycol chitosan8 and alkylated poly(L-lysine citramide)11, although the effects of depolymerisation of the carbohydrate backbone was not explored in the work done on these carbohydrates8, 9, 11. However, two different molecular weights of N-lauroyl 6-carboxymethyl chitosan, with one molecular weight class being investigated at two different levels of lauroyl and carboxymethyl substitution, have been reported by Miwa and others11 as “micellar” carriers of the hydrophobic drug paclitaxel. The paclitaxel formulation described by these workers however is prepared by the probe sonication of N-lauroyl 6-carboxymethyl chitosan and paclitaxel in a 10% v/v ethanol solution. The removal of ethanol by dialysis was attempted but not confirmed by these workers and final N-lauroyl 6-carboxymethyl chitosan—paclitaxel formulations were described as “turbid” with particle size ranges of between 30 and 300 nm and a mean particle size of between 32 and 82 nm. In contrast, the invention disclosed herein relates to the attributes of a solubilising polymer which produces optically clear solutions (devoid of appreciable light scattering) when hydrophobic drugs are added to an aqueous phase (devoid of organic solvents) in the presence of the solubilising polymer. Miwa and others on the other hand report that the precursor to N-lauroyl 6-carboxymethyl chitosan which contains no hydrophobic chain—carboxymethyl chitin “yielded a clear solution and the scattering phenomena detected in the case of micellar solution were not observed in the carboxymethyl chitin solution”11. The present invention thus differs from that reported by Miwa and others11 in that an aqueous optically clear solution is prepared from the polymer and appropriate concentrations of poorly soluble drugs. Organic solvents are also not required in the preparation of the present solutions.
Hydrophobically modified chitosans soluble in dilute acid solutions have also been reported12, 13. Other hydrophobically modified carbohydrates have been reported to yield particulate14-19 dispersions in aqueous media as opposed to water soluble materials13—namely palmitoyl glycol chitosan14, 15, deoxycholic acid modified chitosan16, 17 and cholesterol bearing pullulans18, 19 or alternatively aqueous insoluble gel-like materials20, 21.
While the advantageous influence of depolymerisation, controlled hydrophilic substitution, and controlled hydrophobic substitution of carbohydrates on the production of an optically clear solution with hydrophobic drugs has not previously been described, reports on the individual influences of depolymerisation, hydrophobic substitution and hydrophilic substitution on polymer behaviour can be found in the literature. There is an indirect relationship between the length of hydrophobic pendant groups and water solubility in the case of hydrophobised starches22 and hydrophobised ethyl celluloses20. This parameter also has a direct influence on the degree of polymer aggregation when in solution in the case of amphiphilic chitosans9 and dextrans23 as well as on the solubilising properties of hydrophobically modified chitosans9. The degree of hydrophobic substitution has also been reported to have an indirect influence on the aqueous solubility of starch derivatives22 and affects the flow properties of hydroxypropyl guar gums.
The balance of hydrophobic and hydrophilic substitution has also been reported to affect a number of polymer properties. An increase in hydrophobic substitution from 20 substituents in every 100 monomers to 90 substituents in every 100 monomers with an associated decrease in the level of carboxymethyl substituents from 200 substituents in every 100 monomers to 140 substituents in every 100 monomers decreased the association of paclitaxel with the N-lauroyl 6-carboxymethyl chitosan colloids11, indicating that a more hydrophobic polymer promoted association of paclitaxel with the chitosan based colloid. The balance between the level of hydrophobic and hydrophilic modification also affected the flow properties of amphiphilic hydroxyethylcelluloses24 and an optimum hydrophobic modification level for amphiphilic chitosans has been identified when these materials are used to prevent wool shrinkage during washing25.
With regard to amphiphilic polymer molecular weight alone this has been shown to have an indirect effect on the emulsifying activity of hydrophobised starches26 and an optimum molecular weight has been identified for amphiphilic chitosans bearing deoxycholic acid pendant groups in the context of DNA—chitosan nanoparticles fabricated for gene delivery27. Also the molecular weight of hydrophobised (C6-acyl) dextrans influenced the phase separation of these systems with the high molecular weight material being more likely to phase separate23. The molecular weight of hydrophobic hydroxypropyl guar gums28 was found to influence their flow properties. However, the molecular weight of N-lauroyl 6-carboxymethyl chitosan polymers did not affect their ability to encapsulate paclitaxel within the chitosan based colloid11.
Returning to the work of Zhang and others on acyl dextrans23, the main purpose of this work was to “prepare a family of polymer pairs in which the compatibility in aqueous solution could be varied in subtle ways” with a view to applying the results to the development of adhesives. The authors conclude that the tendency for dextran and hydrophobically modified dextran to phase separate increases with molecular weight, degree of hydrophobic substitution and hydrophobic chain length23. It should be noted that Zhang and others23 did not explore the effect of molecular weight on the phase separation of hydrophobically and hydrophilically modified dextrans.
It is an object of embodiments of the present invention to obviate or mitigate at least one or more of the aforementioned problems.
It is a further object of embodiments of the present invention to provide a polymer for solubilising hydrophobic materials such as drugs.